The myelin proteolipid protein (PLP) is a well characterized CNS myelin protein, which constitutes 50% of the myelin membrane (Eng et al. 1968; Norton and Poduslo, 1973). However, it is expressed also in embryos, neurons and other nonmyelinating cells. Why is this? The current studies focus on the hypothesis that this protein has an additional role that impacts signaling in cells. We hypothesize that PLP interacts with integrins and neurotransmitter receptors, and thereby modulates a series of events in developing brain as well as in the mature brain. This hypothesis derives from studies supported by this grant during the past funding period, in which we demonstrated a direct interaction of PLP with v integrin and the formation of a complex of PLP with av integrin and neurotransmitter receptors in oligodendrocyte progenitor cells, which modulates their interaction with the extracellular matrix (Gudz et al. 2002; 2006). In the proposed studies, we will test the hypothesis that PLP interaction with integrins and neurotransmitter receptors in embryonic and early postnatal development modulates oligodendrocyte and neuron development. In order to investigate this hypothesis, we will pursue the following aims. In aim 1, we will identify the proteins in the PLP signaling complex and the signaling pathways involved. In aim 2, we will investigate the role of the specific proteins in the PLP/integrin/ neurotransmitter receptor complex that mediates oligodendrocyte progenitor cell migration in cultured oligodendrocytes. In aim 3, we will investigate the role of the specific proteins in the PLP/integrin/neurotransmitter receptor modulation of neuron and oligodendrocyte progenitor cell migration in vivo. We will analyze Plp-null, v integrin null and GluR2-null mice, after crossing our Plp-Enhanced Green Fluorescent Protein (EGFP) transgene into them. For some studies we will analyze a conditional knockout mouse that selectively ablates the av integrin in oligodendrocyte progenitor cells in the developing brain. In the final aim, we will analyze the consequences of these null mutations for migration of neurons and oligodendrocyte progenitor cells in cerebellum, optic nerve and embryonic telencephalon, using real time imaging.